Regulation of H. Pylori Virulance by Dietary Factors that Impact Gastric Cancer

影响胃癌的饮食因素对幽门螺杆菌毒力的调节

• 批准号: 9274163
• 负责人: TIMOTHY L COVER
• 金额: $ 28.2万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9274163
• 关键词: Affect; Animal Model; Bacterial Infections; Bacterial Proteins; Cancer Etiology; Carcinogens; Cell Culture Techniques; Cessation of life; Characteristics; Chronic; Collaborations; Development; Diet; Diet Modification; Dietary Factors; Disease Outcome; Employee Strikes; Environment; Environmental Risk Factor; Epidemiology; Epidermal Growth Factor Receptor; Epithelial Cells; Exhibits; Funding; Gastric Adenocarcinoma; Gastric lymphoma; Genes; Genetic; Genetic Variation; Gerbils; Goals; Gram-Negative Bacteria; Helicobacter Infections; Helicobacter pylori; Histopathology; Human; Incidence; Individual; Infection; Inflammation; Iron; Lead; Lesion; Link; Malignant Neoplasms; Membrane Proteins; Modeling; Molecular; Organ Culture Techniques; Organoids; Pathogenesis; Pathogenicity Island; Pathway interactions; Patients; Pattern; Peptic Ulcer; Persons; Population; Premalignant; Prevention; Prevention approach; Prevention therapy; Production; Proteins; Proteomics; Regulation; Research; Resources; Risk; Risk Factors; Role; Sodium Chloride; Stomach; Surface; Up-Regulation; Variant; Virulence; Work; World Health Organization; beta catenin; cancer risk; carcinogenesis; carcinogenicity; experimental study; high salt diet; improved; in vivo; iron deficiency; malignant stomach neoplasm; novel strategies

Persistent colonization of the human stomach with the Gram-negative bacterium Helicobacter pylori is associated with an increased risk for the development of gastric adenocarcinoma. Gastric cancer is the second leading cause of cancer-related death worldwide, and H. pylori has been classified as a type I carcinogen by the World Health Organization. Among H. pylori-infected persons, the risk of gastric cancer is determined by multiple variables, including characteristics of H. pylori strains, host genetic characteristics, and environmental factors. The long-term goal of this work is to define the mechanisms by which H. pylori infection can lead to gastric cancer, and to develop improved approaches for identifying individuals who have an increased risk for gastric cancer. In previous studies, we have shown that persons infected with GagA-positive H. pylori strains have an increased gastric cancer risk compared to persons infected with GagA-negative strains. H. pylori-induced gastric cancer in the Mongolian gerbil model is GagA-dependent, and we have shown that both a high-salt diet and a low-iron diet increase the risk of gastric cancer in H. pylori-infected gerbils. Furthermore, we have shown that exposure of H. pylori to high-salt conditions stimulates upregulation of GagA production. In this project, we propose to investigate further the regulation of H. pylori virulence by dietary factors that impact gastric cancer. Aim 1 proposes to define the roles of three salt-regulated H. pylori outer membrane proteins (HopQ and two VacA-Iike proteins) in gastric cancer development. We will use multiple experimental approaches, including conventional cell culture, gastric organ culture and gastric organoid culture, and the Mongolian gerbil model of H. pylori-induced gastric cancer. Aim 2 will identify shared .features of the pathways by which a high-salt diet and a low-iron diet augment gastric cancer risk in the H. pylori-infected gerbil model. Aim 3 will analyze regulation of salt-responsive H. pylori genes in vivo and analyze adaptation of H. pylori to a carcinogenic gastric environment. These aims will interdigitate with work proposed in Projects 1 and 2 (which each focus on H. pylori-induced epithelial cell alterations) and will utilize both the Gastric Histopathology and Proteomics Cores. These studies should lead to important advances in our understanding of the molecular mechanisms by which H. pylori infection and relevant dietary factors promote the development of gastric cancer. Ultimately, these studies should lead to advances in the prevention and therapy of malignancies that develop in the setting of chronic inflammation.

人类胃的持续定殖幽门螺杆菌与幽门螺杆菌的幽门螺杆菌的持续定殖与胃腺癌发展的风险增加有关。胃癌是全球与癌症相关死亡的第二大主要原因，幽门螺杆菌已被世界卫生组织归类为I型致癌物。在幽门螺杆菌感染的人中，胃癌的风险取决于多个变量，包括幽门螺杆菌菌株的特征，宿主遗传特征和环境因素。这项工作的长期目标是定义幽门螺杆菌感染可以导致胃癌的机制，并开发改进的方法，以识别患有胃癌风险增加的个体。在先前的研究中，我们已经表明，与感染GAGA阴性菌株的人相比，感染GAGA阳性幽门螺杆菌菌株的人的胃癌风险增加。幽门螺杆菌诱导的蒙古语沙鼠模型中的胃癌是GAGA依赖性的，我们已经表明，高盐饮食和低铁饮食都会增加幽门螺杆菌感染的香鼠的胃癌风险。此外，我们已经表明，幽门螺杆菌暴露于高盐的条件下，刺激了GAGA产生的上调。在该项目中，我们建议通过影响胃癌的饮食因素进一步调查幽门螺杆菌毒力。 AIM 1提议定义三个角色 胃癌发育中盐调节的幽门螺杆菌外膜蛋白（HOPQ和两种VACA-IKE蛋白）。我们将使用多种实验方法，包括常规细胞培养，胃器官培养和胃器官培养物，以及幽门螺杆菌诱导的胃癌的蒙古Gerbil模型。 AIM 2将确定幽门螺杆菌感染的Gerbil模型中高盐饮食和低铁饮食增强胃癌风险的途径的共享。 AIM 3将分析体内盐响应性幽门螺杆菌基因的调节，并分析幽门螺杆菌对致癌性胃环境的适应。这些目的将与项目1和2中提出的工作（每个都集中在幽门螺杆菌诱导的上皮细胞改变）中相互互动，并将同时利用胃部病理学和蛋白质组学核心。这些研究应导致我们对幽门螺杆菌感染和相关饮食因素促进胃癌发展的分子机制的理解的重要进展。最终，这些研究应导致预防和治疗在慢性炎症环境中发展的恶性肿瘤的进步。